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p53 Mutation Arising in Arg72 Allele in the Tumorigenesis and Development of Carcinoma of the Urinary Tract¹

Departments of Pathology II [M. F., T. T., M. M., A. K., Y. O.] and Urology [T. S.], Kochi Medical School, Nankoku, Kochi 783-8505; Division of Urology, Kochi Takasu Hospital, Kochi 780-8122 [N. T.]; and Division of Urology, Fujisaki Hospital, Karatsu, Saga 847-0011 [M. K.], Japan

Purpose: It is known that a common p53 polymorphism, encodingeither proline (Pro) or arginine (Arg) at residue 72, produces marked change in the structure of p53. Furthermore, the Arg72-containing allele is preferentially mutated and retained in various human tumors, suggesting that polymorphic residue within p53 modifies mutant behavior. We studied to determine whether Arg72 could be a risk factor for p53 mutations in human transitional cell carcinomas (TCCs). In addition, the relationship between the status of p53 codon 72 polymorphism and clinicopathological factors of this tumor were also analyzed.

Experimental Design: We analyzed the correlation between the p53 mutations and genotypes of its codon 72 using genomic DNAs from the TCCs by direct DNA sequencing. Loss of heterozygosity was determined using a p53 microsatellite marker (TP53) amplified by PCR.

Results: There was a bias to mutate and express the Arg allele in the p53 -mutated TCCs arising in individuals with heterozygosity (Pro/Arg). The Arg72-containing allele was preferentially retained in these tumors. The prevalence of cases with p53 mutations within Arg72-containing allele was higher for advanced-stage TCCs (² = 5.320, P = 0.021) than for TCCs with those arising in Pro72-containing allele.

Conclusions: Our in vivo findings suggested that p53 mutation alleles containing Arg72 are preferentially selected during tumorigenesis and affect mutant behavior in TCCs, and revealed that TCCs with p53 mutation arising in Arg72-containing allele became progressively more abundant with increase in tumor stage.

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